Background: Intramuscular fat(IMF) content is a vital parameter for assessing pork quality. Increasing evidence has shown that microRNAs(miRNAs) play an important role in regulating porcine IMF deposition. Here, a nov...Background: Intramuscular fat(IMF) content is a vital parameter for assessing pork quality. Increasing evidence has shown that microRNAs(miRNAs) play an important role in regulating porcine IMF deposition. Here, a novel miRNA implicated in porcine IMF adipogenesis was found, and its effect and regulatory mechanism were further explored with respect to intramuscular preadipocyte proliferation and differentiation.Results: By porcine adipose tissue miRNA sequencing analysis, we found that miR-146a-5p is a potential regulator of porcine IMF adipogenesis. Further studies showed that miR-146a-5p mimics inhibited porcine intramuscular preadipocyte proliferation and differentiation, while the miR-146a-5p inhibitor promoted cell proliferation and adipogenic differentiation. Mechanistically, miR-146a-5p suppressed cell proliferation by directly targeting SMAD family member 4(SMAD4) to attenuate TGF-β signaling. Moreover, miR-146a-5p inhibited the differentiation of intramuscular preadipocytes by targeting TNF receptor-associated factor 6(TRAF6) to weaken the AKT/mTORC1 signaling downstream of the TRAF6 pathway.Conclusions: MiR-146a-5p targets SMAD4 and TRAF6 to inhibit porcine intramuscular adipogenesis by attenuating TGF-β and AKT/mTORC1 signaling, respectively. These findings provide a novel miRNA biomarker for regulating intramuscular adipogenesis to promote pork quality.展开更多
CD8＋ cytotoxic T lymphocyte （CTL） exhaustion is a chief issue for ineffective virus elimination in chronic infectious diseases. We generated novel ovalbumin （OVA）-specific OVA-Texo and HIV-specific Gag-Texo vacci...CD8＋ cytotoxic T lymphocyte （CTL） exhaustion is a chief issue for ineffective virus elimination in chronic infectious diseases. We generated novel ovalbumin （OVA）-specific OVA-Texo and HIV-specific Gag-Texo vaccines inducing therapeutic immunity. To assess their therapeutic effect in chronic infection, we developed a new chronic infection model by i.v. infecting C57BL/6 mice with the OVA-expressing adenovirus AdVova. During chronic AdVova infection, mouse CTLs were found to express the inhibitory molecules programmed cell-death protein-1 （PD-1） and lymphocyte-activation gene-3 （LAG-3） and to be functionally exhausted, showing a significant deficiency in T-cell proliferation, IFN-7 production and cytolytic effects. Naive CD8＋ T cells upregulated inhibitory PD-ligand 1 （PD-L1）, B- and T-lymphocyte attenuator and T-cell anergy-associated molecules （Grail and Itch） while down-regulating the proliferative response upon stimulation in mice with chronic infection. Remarkably, the OVA-Texo vaccine counteracted T-cell anergy and converted CTL exhaustion. The latter was associated with （i） the upregulation of a marker for CTL functionality, diacetylated histone-H3 （diAcH3）, （ii） a fourfold increase in CTLs, occurring independent of host DCs or CD4＋ T cells, and （iii） the restoration of CTL IFN-7 production and cytotoxicity. In vivo OVA-Texo-stimulated CTLs upregulated the activities of the mTORC1 pathway-related molecules Akt, S6, elF4E and T-bet, and treatment of the CTLs with an mTORC1 inhibitor, rapamycin, significantly reduced the OVA-Texo- induced increase in CTLs. Interestingly, OVA-Texo-mediated CD40L signaling played a critical role in the observed immunological effects. Importantly, the Gag-Texo vaccine induced Gag-specific therapeutic immunity in chronic infection. Therefore, this study should have a serious impact on the development of new therapeutic vaccines for human immunodeficiency virus （HIV-1） infection.展开更多
The mechanistic target of rapamycin complex 1(mTORC1)integrates various types of signal inputs,such as energy,growth factors,and amino acids to regulate cell growth and proliferation mainly through the 2 direct downst...The mechanistic target of rapamycin complex 1(mTORC1)integrates various types of signal inputs,such as energy,growth factors,and amino acids to regulate cell growth and proliferation mainly through the 2 direct downstream targets,eukaryotic translation initiation factor 4 E-binding protein 1(4 EBP1)and ribosomal protein S6 kinase 1(S6 K1).Most of the signal arms upstream of mTORCl including energy status,stress signals,and growth factors converge on the tuberous sclerosis complex(TSC)-Ras homologue enriched in brain(Rheb)axis.Amino acids,however,are distinct from other signals and modulate mTORCl using a unique pathway.In recent years,the transmission mechanism of amino acid signals upstream of mTORCl has been gradually elucidated,and some sensors or signal transmission pathways for individual amino acids have also been discovered.With the help of these findings,we propose a general picture of recent advances,which demonstrates that various amino acids from lysosomes,cytoplasm,and Golgi are sensed by their respective sensors.These signals converge on mTORCl and form a huge and complicated signal network with multiple synergies,antagonisms,and feedback mechanisms.展开更多
Sarcopenia is common in patients with many physiological or pathological conditions, especially in aging people. Nutrition plays an important role in the prevention and treatment of sarcopenia. Sarcopenia is often rel...Sarcopenia is common in patients with many physiological or pathological conditions, especially in aging people. Nutrition plays an important role in the prevention and treatment of sarcopenia. Sarcopenia is often related to insufficient protein intake in the elderly. Muscle protein synthesis occurs mainly through mTORC1 pathway, and degradation occurs by ubiquitination-mediated pathways. This review summarizes the growing body of evidence, including substantial clinical trials, which increasing the protein intake can serve as the basis for preventing and managing muscle loss in patients with sarcopenia. Supplementation of essential amino acids (EAA), branched chain amino acids (BCAA), and especially leucine-rich whey protein may promote muscle protein synthesis by activating the mTORC1 signaling pathway, and may inhibit protein degradation by decreasing ubiquitin-mediated degradation. Taking in sufficient energy and protein and engaging in active exercise are the main methods of stimulating muscle protein synthesis and preventing or managing sarcopenia. Therefore, it is necessary to strengthen research on the use of protein supplements for not only elderly patients, but also those with tumor cachexia and other diseases related to sarcopenia.展开更多
基金supported by grants from the National Natural Science Foundation (31872979, 31572366)the National Key Research and Development Program of China (2017YFD0502002)the National Basic Research Programs of China (2015CB943102)。
文摘Background: Intramuscular fat(IMF) content is a vital parameter for assessing pork quality. Increasing evidence has shown that microRNAs(miRNAs) play an important role in regulating porcine IMF deposition. Here, a novel miRNA implicated in porcine IMF adipogenesis was found, and its effect and regulatory mechanism were further explored with respect to intramuscular preadipocyte proliferation and differentiation.Results: By porcine adipose tissue miRNA sequencing analysis, we found that miR-146a-5p is a potential regulator of porcine IMF adipogenesis. Further studies showed that miR-146a-5p mimics inhibited porcine intramuscular preadipocyte proliferation and differentiation, while the miR-146a-5p inhibitor promoted cell proliferation and adipogenic differentiation. Mechanistically, miR-146a-5p suppressed cell proliferation by directly targeting SMAD family member 4(SMAD4) to attenuate TGF-β signaling. Moreover, miR-146a-5p inhibited the differentiation of intramuscular preadipocytes by targeting TNF receptor-associated factor 6(TRAF6) to weaken the AKT/mTORC1 signaling downstream of the TRAF6 pathway.Conclusions: MiR-146a-5p targets SMAD4 and TRAF6 to inhibit porcine intramuscular adipogenesis by attenuating TGF-β and AKT/mTORC1 signaling, respectively. These findings provide a novel miRNA biomarker for regulating intramuscular adipogenesis to promote pork quality.
文摘CD8＋ cytotoxic T lymphocyte （CTL） exhaustion is a chief issue for ineffective virus elimination in chronic infectious diseases. We generated novel ovalbumin （OVA）-specific OVA-Texo and HIV-specific Gag-Texo vaccines inducing therapeutic immunity. To assess their therapeutic effect in chronic infection, we developed a new chronic infection model by i.v. infecting C57BL/6 mice with the OVA-expressing adenovirus AdVova. During chronic AdVova infection, mouse CTLs were found to express the inhibitory molecules programmed cell-death protein-1 （PD-1） and lymphocyte-activation gene-3 （LAG-3） and to be functionally exhausted, showing a significant deficiency in T-cell proliferation, IFN-7 production and cytolytic effects. Naive CD8＋ T cells upregulated inhibitory PD-ligand 1 （PD-L1）, B- and T-lymphocyte attenuator and T-cell anergy-associated molecules （Grail and Itch） while down-regulating the proliferative response upon stimulation in mice with chronic infection. Remarkably, the OVA-Texo vaccine counteracted T-cell anergy and converted CTL exhaustion. The latter was associated with （i） the upregulation of a marker for CTL functionality, diacetylated histone-H3 （diAcH3）, （ii） a fourfold increase in CTLs, occurring independent of host DCs or CD4＋ T cells, and （iii） the restoration of CTL IFN-7 production and cytotoxicity. In vivo OVA-Texo-stimulated CTLs upregulated the activities of the mTORC1 pathway-related molecules Akt, S6, elF4E and T-bet, and treatment of the CTLs with an mTORC1 inhibitor, rapamycin, significantly reduced the OVA-Texo- induced increase in CTLs. Interestingly, OVA-Texo-mediated CD40L signaling played a critical role in the observed immunological effects. Importantly, the Gag-Texo vaccine induced Gag-specific therapeutic immunity in chronic infection. Therefore, this study should have a serious impact on the development of new therapeutic vaccines for human immunodeficiency virus （HIV-1） infection.
基金supported by grants from the Modern Agroindustry Technology Research System of China(No.CARS-36)Taishan Scholar Project of Shandong Province。
文摘The mechanistic target of rapamycin complex 1(mTORC1)integrates various types of signal inputs,such as energy,growth factors,and amino acids to regulate cell growth and proliferation mainly through the 2 direct downstream targets,eukaryotic translation initiation factor 4 E-binding protein 1(4 EBP1)and ribosomal protein S6 kinase 1(S6 K1).Most of the signal arms upstream of mTORCl including energy status,stress signals,and growth factors converge on the tuberous sclerosis complex(TSC)-Ras homologue enriched in brain(Rheb)axis.Amino acids,however,are distinct from other signals and modulate mTORCl using a unique pathway.In recent years,the transmission mechanism of amino acid signals upstream of mTORCl has been gradually elucidated,and some sensors or signal transmission pathways for individual amino acids have also been discovered.With the help of these findings,we propose a general picture of recent advances,which demonstrates that various amino acids from lysosomes,cytoplasm,and Golgi are sensed by their respective sensors.These signals converge on mTORCl and form a huge and complicated signal network with multiple synergies,antagonisms,and feedback mechanisms.
基金NSFC grants from the National Natural Science Foundation of China (No. 81673167) to Hong xia Xu.
文摘Sarcopenia is common in patients with many physiological or pathological conditions, especially in aging people. Nutrition plays an important role in the prevention and treatment of sarcopenia. Sarcopenia is often related to insufficient protein intake in the elderly. Muscle protein synthesis occurs mainly through mTORC1 pathway, and degradation occurs by ubiquitination-mediated pathways. This review summarizes the growing body of evidence, including substantial clinical trials, which increasing the protein intake can serve as the basis for preventing and managing muscle loss in patients with sarcopenia. Supplementation of essential amino acids (EAA), branched chain amino acids (BCAA), and especially leucine-rich whey protein may promote muscle protein synthesis by activating the mTORC1 signaling pathway, and may inhibit protein degradation by decreasing ubiquitin-mediated degradation. Taking in sufficient energy and protein and engaging in active exercise are the main methods of stimulating muscle protein synthesis and preventing or managing sarcopenia. Therefore, it is necessary to strengthen research on the use of protein supplements for not only elderly patients, but also those with tumor cachexia and other diseases related to sarcopenia.
